Carbon tetrachloride (CCl4) is generally hepatotoxic to mammals. When given intraperitoneally to a rat, CCl4 usually causes a multifaceted lesion with centrilobular necrosis, midzonal lipid accumulation and peripheral regeneration. Under these circumstances, it is difficult to evaluate the factors directly involved in the development of parenchymal necrosis. Recently it has been discovered that various drug pretreatments can enhance CCl4 hepatotoxicity, so that massive hepatic necrosis ensues. Contrariwise, pretreatmet with various foreign materials has been found to ameliorate the hepatotoxic response, so that little or no necrosis follows a CCl4 challenge. By examining conditions associated with these "all-or-none" hepatic responses to CCl4, one can more realistically evaluate the factors currently believed to contribute to hepatocellular necrosis. Accordingly, the proposed research intends to utilize pharmacological, biochemical, and morphological techniques (sleeping and paralysis times, determinations of hepatic microsomal TPNH-cytochrome c reductase activity and cytochrome P-450, and light and electron microscopy) to determine the liver alterations induced by the various pretreatments and to evaluate the effects of such pretreatments on CCl4 hepatotoxicity. Specifically, the experiments are designed to explore the role of hepatocellular smooth-surfaced membranes and their associated drug-metabolizing enzyme systems in the development of hepatic parenchymal necrosis. Other studies will examine the protection afforded by various foreign substances against CCl4 hepatotoxicity and will seek to determine the role of hepatic sinusoidal lining cells in this process. Finally, the projected investigations will evaluate the hepatotoxicity of other haloalkanes along similar lines.